PROJECT SUMMARY/ABSTRACT This proposal will use novel marine natural products for the study and treatment of pain, depression, anxiety, and comorbid instances of pain and affective disturbances. Recent evidence demonstrates a significant interaction between chronic pain and depression/anxiety. In particular, chronic pain (e.g. fibromyalgia, chronic lower back pain, painful bladder syndrome) seems to be linked both epidemiologically and biologically with depression/anxiety. In this situation, the separate diseases actually potentiate one another to create an acutely dangerous pathological environment. Interestingly, this overlap presents an important new mechanistic and therapeutic target for the treatment of patients. That is, these common mechanisms might be useful for the development of non-opioid treatments that show efficacy against both diseases with a single agent. This scenario would be doubly advantageous in that it could be used as a prophylactic treatment in the early stages of a single disorder to prevent the development of the secondary disease (i.e. pain or depression). We aim to test the hypothesis that the common mechanisms of pain and depression can be used to target these disorders with novel compounds directed at serotonin G-protein coupled receptors (GPCRs). Serotonin is a brain neurochemical and serotonin receptors are one of the most common targets in psychiatric disease and more recently in chronic pain disorders. Most studies using serotonin-targeting agents have used established neurotransmitter re-uptake modulators, which can have unintended effects in a receptor-specific manner. That is, increased signaling through one receptor may be anti-depressant in one anatomical location but hyperalgesic in another. In order to understand the potential for antagonistic or synergistic actions of specific receptors, we aim to test compounds for both anti-depressant and analgesic properties in tandem as well as in a model of comorbid chronic pain and depression/anxiety during the initial testing. We will be testing extracts, fractions, and purified compounds from existing and new microbial collections from the highly diverse waters of Panama and Curaao. The discovery of natural products from microbial environments is an emerging field of research but has yielded a large number of interesting and important compounds in a variety of disease states. Predominately, studies have focused on the discovery of toxic compounds for their utility as anti-bacterial, anti- fungal, or anti-cancer agents. This proposal, however, will examine extracts from microbes for psychoactive compounds and their ability to modulate serotonin GPCRs, to treat pain and depression, using in vivo mouse models following in vitro screening against GPCRs. The expected outcomes of this research would be identification of novel ligands for psychoactive GPCRs and an increased understanding of the shared mechanisms of pain and depression/anxiety.